`
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`Cabazitaxel Monograph
`
`Cabazitaxel (Jevtana)
`National Drug Monograph
`March 2011
`VA Pharmacy Benefits Management Services,
`Medical Advisory Panel, and VISN Pharmacist Executives
`
`The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary
`decisions. These documents will be updated when new clinical data warrant additional formulary discussion.
`Documents will be placed in the Archive section when the information is deemed to be no longer current.
`
`
`Executive Summary:
`Cabazitaxel is a novel taxane that shows anticancer activity against docetaxel sensitive and
`resistant cells in vitro. It is thought to be a weak substrate for p-glycoprotein, the main
`mechanism for taxane resistance.
`
`It was approved by the FDA, in combination with prednisone, for the treatment of patients with
`castrate-resistant prostate cancer who progressed during or following therapy with a docetaxel
`containing regimen.
`
`Efficacy
`In a phase III trial comparing cabazitaxel (25mg/m2) plus prednisone to mitoxantrone (12 mg/m2)
`plus prednisone in patients with castrate-resistant prostate cancer who progressed during or
`following therapy with at least 225 mg/m2 of docetaxel (suggesting a minimum of 12 weeks of
`treatment), cabazitaxel met its primary endpoint of increasing overall survival. The median
`overall survival of 15.1 months for cabazitaxel versus 12.7 months for mitoxantrone represents a
`30% decrease in the relative risk of death (Hazard Ratio 0.70 95%CI 0.59-0.83).
`
`Safety
`There was a higher incidence of treatment related deaths in the cabazitaxel arm. The most
`common fatal adverse event was infection in 5 patients, 4 of whom had neutropenia and 1 with
`neutropenic fever. Four of the five fatal infections occurred after one dose. The fatal adverse
`event in 4 patients was renal failure.
`
`Serious adverse events included: neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea,
`fatigue, and asthenia.
`
`Boxed warnings exist for neutropenic deaths and hypersensitivity reactions. Cabazitaxel is
`contraindicated in patients with a previous history of hypersensitivity reactions to drugs
`formulated with polysorbate 80.
`
`
`
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
`
`1
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`MYLAN - CORRECTED EXHIBIT 1067
`Mylan Laboratories Limited v. Aventis Pharma S.A. IPR2016-00712
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`Cabazitaxel Monograph
`
`Introduction
`
`The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability,
`efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating cabazitaxel
`for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify
`parameters for its rational use in the VA.
`Pharmacology/Pharmacokinetics
`Cabazitaxel is new generation taxane. It binds to microtubules promoting tubulin assembly,
`stabilizes microtubules resulting in cell cycle arrest, and inhibits cell proliferation. In pre-clinical
`trials, cabazitaxel had activity in docetaxel sensitive and docetaxel resistant cell lines and was
`shown to cross the blood brain barrier. The most widely studied mechanism of inherited and
`acquired multidrug resistance to taxanes is over expression of p-glycoprotein. Sensitivity of
`docetaxel-resistant cell lines to cabazitaxel suggests it is a weak substrate for p-glycoprotein.
`
`
`
`Cabazitaxel Pharmacokinetics
`Drug
`Extensively in liver, primarily CYP3A4/5 and to a lesser extent CYP2C8. 3 active
`metabolites and 17 others identified; all are excreted in urine and feces.
`Cabazitaxel is not a CYP inducer and has a low potential to inhibit drugs that are
`substrates for CYP isoenzymes
`80% of IV dose eliminated within 2 weeks, mainly excreted in feces as
`metabolites; 3.7% of an IV dose is eliminated renally
`Three compartment model with  half-life=4 minutes, β half-life=2 hours, and γ
`half-live=95 hours.
`
`Table #1
`Parameter
`
`Metabolism
`
`Elimination
`
`Half-life
`
`
`
`FDA Approved Indication(s)
`Indicated in combination with prednisone for the treatment of patients with hormone-refractory
`prostate cancer previously treated with docetaxel-containing treatment regimen.
`
`Potential Off-label Uses
`This section is not intended to promote any off-label uses. Off-label use should be evidence-
`based. See VA PBM-MAP and Center for Medication Safety’s Guidance on “Off-label”
`Prescribing (available on the VA PBM Intranet site only).
`
`First-line therapy of hormone-refractory (castrate-resistant) prostate cancer in place of docetaxel.
`
`Current Alternatives
`Cabazitaxel is the only drug with an FDA indication for castrate-resistant prostate cancer in
`patients who progressed during or following therapy with a docetaxel containing regimen.
`Multiple regimens have been studied in patients with taxane resistant disease, but none have
`provided a survival benefit. The best alternative to cabazitaxel therapy is participation in a
`clinical trial.
`
`
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
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`Cabazitaxel Monograph
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`Dosage and Administration
`Pre-medications (at least 30 minutes prior to cabazitaxel to reduce the risk/severity of
`hypersensitivity reactions):
` Antihistamine IV (e.g. diphenhydramine 25mg or equivalent)
` Corticosteroid IV (dexamethasone 8mg or equivalent)
` H2 antagonist IV (ranitidine 50mg or equivalent)
`
`Preparation
` First Dilution- Mix the vial of cabazitaxel 60mg/1.5ml with the entire contents of the supplied
`diluents. Limit foaming during dilution; do not shake. Final concentration of cabazitaxel
`is 10mg/mL.
` Second Dilution- Withdraw the recommended dose from First Dilution and further dilute in
`250mL PVC-free container with either 0.9% sodium chloride solution or 5% dextrose
`solution. If a dose needed is greater than 65 mg, use a larger volume of infusion solution so
`that the concentration of cabazitaxel does not exceed 0.26 mg/mL. The final concentration of
`cabazitaxel should be between 0.1 mg/mL and 0.26 mg/mL. Use this final solution within 8
`hours stored at room temperature or within a total of 24 hours if refrigerated (included
`infusion time).
`
`
`Dose
`
`Initial dose of 25 mg/m2 over 1 hour as an intravenous infusion every three weeks in
`combination with prednisone 10 mg orally daily throughout treatment
` Dose Modifications- reduce dose to 20 mg/m2 if patient experiences any of the following
`toxicities:
`Toxicity
`Prolonged Grade ≥Grade 3 neutropenia
`(greater than 1 week) despite appropriate
`medication including G-CSF
`Febrile neutropenia
`
`Dosage Modification
`Delay treatment until neutrophil count is
`>1,500 cells/mm3, then reduce dose to 20
`mg/m2. Use G-CSF secondary prophylaxis
`Delay treatment until improvement or
`resolution, and until neutrophil count is
`>1,500 cells/mm3, then reduce dose to 20
`mg/m2. Use G-CSF secondary prophylaxis
`Delay treatment until improvement or
`resolution, then reduce dose to 20 mg/m2.
`
`Grade ≥ 3 diarrhea or persisting diarrhea
`despite appropriate medications, fluids, and
`electrolyte replacement
`
`Use in Special Populations
` Renal Impairment- No formal trials have been conducted in patients with renal impairment.
`Population pharmacokinetic trials included patients with mild to moderate renal impairment;
`no meaningful effects were seen on the pharmacokinetics of cabazitaxel. No data are
`available on the use in patients with severe renal impairment or end-stage renal disease.
` Hepatic Impairment- No formal trials have been conducted in patients with hepatic
`impairment. Cabazitaxel is extensively metabolized by the liver; hepatic impairment is likely
`to increase cabazitaxel concentrations.
`
`
`
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
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`Efficacy
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`
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`Cabazitaxel Monograph
`
`Efficacy Measures
`
`Primary
` Overall Survival (Date of randomization to death)
`
`Secondary
` Progression Free Survival (a composite endpoint of time from randomization to the first date
`of progression [PSA progression, tumor progression, pain progression] or death.
` PSA Response (reduction in PSA serum concentration of ≥50% if baseline PSA is ≥ 20
`mcg/L)
` PSA progression (increase of ≥25% over nadir PSA if the increase in the absolute value is ≥5
`mcg/L in men with no PSA response or ≥50% over nadir for patients showing a PSA
`response)
` Objective Tumor Response (in patients with measurable disease)
` Pain Response (for patients with a present pain intensity [PPI] score of ≥2 or a mean
`analgesic score of ≥10 points at baseline or both) defined as a reduction of 2 points or more
`from baseline median PPI score without increasing analgesic score or decrease of more than
`50% in analgesic use without an increase in pain, maintained for 3 weeks or more.
` Pain Progression (increase in median PPI score of ≥1 point from reference value or an
`increase of ≥25% in the mean analgesic score or requiring palliative radiotherapy.
` Time to Tumor Progression (number of months from randomization until evidence of
`progressive disease by RECIST criteria).
`
`
`Summary of efficacy findings
`Phase III TROPIC trial: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-
`resistant prostate cancer progressing after docetaxel treatment.1
`
`Study Design
`
`International (26 countries)
` Centrally randomized
` Open-label to patients and treating physicians
` Study team blinded to data analysis
`
`Inclusion Criteria
` Pathologically proven prostate cancer
` Documented disease progression during or after completion of docetaxel therapy
`o Measurable disease- required documented disease progression by Response
`Evaluation Criteria in Solid Tumors (RECIST) with at least one visceral or soft tissue
`metastatic lesion
`o Non-measurable disease- rising serum PSA (at least 2 consecutive increases relative
`to a reference value at least 1 week apart) or the appearance of at least one new
`radiographic lesion
` ECOG Performance Status 0-2
` Prior and on-going castration by orchiectomy or LHRH agonist or both
` Antiandrogen withdrawal followed by progression at least 4 weeks (6 weeks in the case of
`bicalutamide) prior to enrollment
`
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
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`Cabazitaxel Monograph
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` Adequate hematological, hepatic, renal and cardiac function
` LVEF more than 50% assessed by MUGA or Echocardiogram
` Concomitant use of bisphosphonates if the dose was stable for 12 weeks before enrollment
` LHRH therapy mandated to be continued throughout trial
`
`Exclusion Criteria
` Previous mitoxantrone therapy,
` Radiotherapy to 40% or more of bone marrow
` Cancer therapy (other than LHRH analogues) within 4 weeks of enrollment
` Grade 2 or higher peripheral neuropathy or stomatitis
` Other serious illness (including secondary cancers)
` History of hypersensitivity to polysorbate 80-containing drugs or prednisone
` Amendment after first 59 patients: Patients receiving a cumulative dose of docetaxel lower
`than 225 mg/m2 (equivalent to 12 weeks of treatment)
`
`
`Treatment
` All patients received prednisone 10mg daily ( or equivalent dose of prednisolone)
` Randomized to either cabazitaxel 25 mg/m2 IV over 1 hour or mitoxantrone 12 mg/m2 IV
`over 15-30 minutes
` Cabazitaxel patients were pre-treated with a single dose of IV antihistamine, corticosteroids
`(8 mg dexamethasone or equivalent) and H2 antagonist (except cimetidine) 30 minutes before
`cabazitaxel.
` Treatment was repeated every 21 days for a maximum of 10 cycles
` Crossover to cabazitaxel was not allowed for the mitoxantrone group
` Prophylactic G-CSF was not allowed for the 1st cycle but was allowed after the first
`occurrence of either neutropenia lasting more than 7 days or neutropenia complicated by
`fever or infection.
`
`
`Baseline Patient Characteristics
`Table #2
`Baseline Characteristics
`
`Characteristic
`Age, median
`≥75 years old
`White
`Asian
`Black
`ECOG 0 or 1
`Metastatic Disease
` Bone metastases
` Visceral metastases
`Pain at baseline
`Previous therapy
` Hormonal
` Number of chemotherapies
` 1
` 2
` >2
`Radiation
`Surgery
`Total dose docetaxel (mg/m2) median
`Progression relative to docetaxel
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
`Mitoxantrone
`N=377
`67 (61-72)
`19%
`83%
`8%
`5%
`91%
`94%
`87%
`25%
`45%
`
`99%
`
`71%
`21%
`8%
`59%
`54%
`529.2
`
`
`Cabazitaxel
`N=378
`68 (62-73)
`18%
`84%
`7%
`5%
`93%
`96%
`80%
`25%
`46%
`
`99%
`
`69^
`25%
`6%
`61%
`52%
`576.6
`
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`Cabazitaxel Monograph
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`28%
`48%
`24%
`
`0.7 (IQR 0.0-2.9)
`
`30%
`42%
`27%
`
`0.8 (IQR 0.0-3.1)
`
`
`
`
`During treatment
`<3 months from last dose
`≥3 months from last dose
`Median time from last docetaxel dose
`to disease progression (months)
`
`
`
`Primary and Secondary Outcomes
`
`Table #3
`Result
`
`Results
`Mitoxantrone
`
`Cabazitaxel
`
`Hazard Ratio
`(95%CI)
`Median Follow-up = 12.8 months (IQR 7.8-16.9)
`12.7 months
`15.1 months
`0.70
`(95%CI 11.6-13.7)
`(95%CI 14.1-16.3)
`(0.59-0.83)
`1.4 months
`2.8 months
`0.74
`(95%CI 1.4-1.7)
`(95%CI 2.4-3.0)
`(0.64-0.86)
`4.4%
`14.4%
`-
`17.8%
`39.2%
`-
`7.7%
`9.2%
`-
`5.4 months
`8.8 months
`0.61
`(95%CI 2.3-10.0)
`(95%CI 3.9-12.0)
`(0.49-0.76)
`3.1 months
`6.4 months
`0.75
`(95%CI 0.91-9.1)
`(95%CI 2.2-10.1)
`(0.63-0.9)
`Not reached
`11.1 months
`0.91
`(95%CI 2.9- not
`(0.69-1.19)
`reached)
`6 cycles
`
`4 cycles
`
`Median Overall
`Survival
`Median Progression
`Free Survival
`Tumor response rate
`PSA response rate
`Pain response rate
`Median time to
`tumor progression
`Median time to PSA
`progression
`Median time to pain
`progression
`
`Median Duration of
`Therapy
`
`
`
`P value for
`comparison
`
`<0.0001
`
`<0.001
`
`0.0005
`0.0002
`0.63
`<0.0001
`
`0.001
`
`0.52
`
`
`
`Cabazitaxel N=371
`61%
`18 (5%)
`0
`
`7 (2%)
`5 (1%)
`0
`1 (<1%)
`3 (1%)
`1 (<1%)
`1 (<1%)
`0
`56%
`
`Deaths during therapy
`
`Mortality
`
`Table #4
`Mitoxantrone N=371
`Events
`74%
`Total deaths
`9 (2%)
`Deaths ≤30 days after last dose of study drug
`6 (2%)*
` Cause: Disease Progression
`
`Adverse events
`1 (<1%)
` Neutropenia & clinical consequence/sepsis
`0
` Cardiac
`1 (<1%)
` Dyspnea
`0
` Dehydration/electrolyte imbalance
`0
` Renal failure
`0
` Cerebral hemorrhage
`0
` Unknown cause
`1 (<1%)
` Motor vehicle accident
`72%
`Deaths >30 days after last dose of study drug
`*includes three patients whose deaths were reported as an adverse event coded as disease progression
`
` A
`
` subgroup analysis of overall survival was performed defined by baseline characteristics. The
`median overall survival for all subgroups favored cabazitaxel. However, for several subgroups
`the 95% confidence intervals crossed over 1. Some that crossed 1 had small numbers of patients
`with wide confidence intervals (e.g. ECOG status 2 and Total docetaxel dose < 225 mg/m2). Of
`note, the Median Overall Survival for the subgroup Progression ≥3 months after docetaxel
`treatment favored cabazitaxel but the upper bound of the confidence interval crossed 1.
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
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`6
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`Cabazitaxel Monograph
`
`
`Disease progression was the primary reason for discontinuation in both groups (Mitoxantrone
`71%, Cabazitaxel 48%) followed by adverse event (Mitoxantrone 8%, Cabazitaxel 18%).
`Twenty-eight percent of cabazitaxel patients completed all 10 cycles versus 12% in the
`mitoxantrone group. There is no information on treatment received following disease progression
`in the cabazitaxel arm; in the mitoxantrone arm it is noted that 12% of patients received a tubulin-
`binding drug following disease progression. There is no information about the collection of any
`quality of life data.
`
`An analysis of the incidence of neutropenia and diarrhea (all grades) in subgroups of patients
`receiving cabazitaxel found differences in the rates of adverse events by age, prior radiotherapy,
`and geographic location. The incidence of neutropenia was greater outside of North America and
`Europe, likely due to differences in investigator treatment of neutropenia and febrile neutropenia.
`
`Supporting Data
`
`Following pre-clinical data in indicating antitumor activity in docetaxel sensitive and resistant
`cell lines and human xenografts, a phase I trial was initiated in patients with solid tumors
`refractory to conventional therapy. Patients were eligible if they received less than two prior
`chemotherapy regiments for metastatic disease. Two of twenty-five patients showed anti-tumor
`responses; both patients had metastatic prostate cancer and one was resistant to prior docetaxel
`therapy.2
`
`Adverse Events (Safety Data)3
`Table #5
`Adverse Events in ≥5% of patients receiving cabazitaxel plus prednisone or
`mitoxantrone plus prednisone
`
`
`Mitoxantrone plus prednisone
`N=371
`
`Grades 3-4
`%
`
`58
`1
`5
`42
`2
`
`<1
`
`<1
`<1
`0
`<1
`0
`0
`
` 3
`
`
`2
`<1
`<1
`<1
`2
`
`
`
`7
`
`All Grades
`%
`
`87
`1
`82
`93
`43
`
` 2
`
`
`
`
`11
`23
`10
`15
`6
`2
`
`27
`12
`6
`9
`3
`5
`
`
`Blood and lymph
` Neutropenia
` Febrile neutropenia
` Anemia
` Leukopenia
` Thrombocytopenia
`Cardiac
` Arrhythmia
`GI Disorders
` Diarrhea
` Nausea
` Vomiting
` Constipation
` Abdominal pain
` Dyspepsia
`General
` Fatigue
` Asthenia
` Pyrexia
` Peripheral edema
` Mucosal inflammation
` Pain
`Infections
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
` 1
`
` 6
`
`
`
`Cabazitaxel plus prednisone
`N=371
`
`Grades 3-4
`%
`
`82
`7
`11
`69
`4
`
`
`2
`2
`1
`2
`0
`
` 5
`
`
`5
`1
`<1
`<1
`1
`
`
`All Grades
`%
`
`94
`7
`98
`96
`48
`
` 5
`
`
`
`
`47
`34
`22
`20
`17
`10
`
`37
`20
`12
`9
`6
`5
`
`
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`

`

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`Cabazitaxel Monograph
`
`3
`8
`
`11
`3
`
`12
`8
`3
`
`3.2
`4
`6
`5
`
` 4
`
`
`1
`
` 4
`
`
`6
`
` 5
`
`
`
`2
`0
`
`<1
`2
`
` 4
`
`
`1
`0
`
`<1
`0
`0
`0
`
` 2
`
`
`0
`
` 1
`
`
`0
`
` 0
`
`
`
`
`<1
`
`
`8
`9
`
`16
`5
`
`16
`11
`7
`
`13
`11
`8
`8
`
`17
`7
`
`12
`11
`
`10
`
` 5
`
`
`
`
`
`6 cycles
`
`1
`<1
`
`<1
`<1
`
` 3
`
`
`1
`0
`
`<1
`0
`<1
`0
`
`<1
`0
`
`<1
`0
`
` 0
`
`
`
`<1
`
`
` 2
`
`
`
`
`
`4 cycles
`
` Urinary tract infection
`Weight decreased
`Metabolism and nutrition
` Anorexia
` Dehydration
`Musculoskeletal
` Back pain
` Arthalgia
` Muscle spasms
`Nervous system
` Peripheral neuropathy
` Dysgeusia
` Dizziness
` Headache
`Renal and Urinary
` Hematuria
` Dysuria
`Respiratory
` Dyspnea
` Cough
`Skin
` Alopecia
`Vascular
` Hypotension
`
`Median Duration of Therapy
`
`Deaths and Other Serious Adverse Events
`Deaths due to causes other than disease progression within 30 days of last study drug occurred in
`18 cabazitaxel patients and 3 mitoxantrone patients.
` Most common fatal adverse reactions in cabazitaxel patients- infections (n=5 cases of sepsis
`or septic shock; all had grade 4 neutropenia and one had febrile neutropenia) and renal failure
`(n=4); 4 out of 5 fatal infection-related adverse events occurred after a single cabazitaxel
`dose. Other fatal reactions included ventricular fibrillation, cerebral hemorrhage, and
`dyspnea.
` 3 patients with a fatal adverse reaction were less than 65 years old; 15 were greater than or
`equal to 65 years old. Patients greater than or equal to 65 years old are more likely to
`experience certain adverse events, for example neutropenia and febrile neutropenia
`
`
`Grade 3-4 serious adverse reactions: neutropenia, leukopenia, anemia, febrile neutropenia,
`diarrhea, fatigue, asthenia.
`
`Common Adverse Events (≥ 10%)
` Anemia
` Leukopenia
` Neutropenia
` Thrombocytopenia
` Diarrhea
` Fatigue
` Nausea
` Vomiting
` Constipation
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
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`Age < 65 years old
`%
`
`30
`89
`15
`8
`5
`3
`2
`
`74
`6
`
` Asthenia
` Abdominal pain
` Hematuria
` Back pain
` Anorexia
` Peripheral neuropathy
` Pyrexia
` Dyspnea
` Dysguesia
` Cough
` Arthalgia
` Alopecia
`
`Other Adverse Events
`
`Table #6
`Event
`
`Fatigue
`Neutropenia
`Asthenia
`Pyrexia
`Dizziness
`Urinary tract infection
`Dehydration
`
`Events in Elderly population
`Age ≥65 years old
`%
`Grades 1-4
`40
`97
`24
`15
`10
`10
`7
`Grade 3-4
`87
`8
`
`Neutropenia
`Febrile neutropenia
`
`
`
`Tolerability
`Table #7 Discontinuations/delays/dose reductions due to adverse events
`
`Cabazitaxel plus prednisone
`Mitoxantrone plus prednisone
`%
`%
`18
`8
`Discontinuation
`28
`15
`Dose Delays
`12
`4
`Dose Reductions
`Most common adverse events leading to discontinuations in cabazitaxel patients: neutropenia
`(2%) and renal failure.
`
`Contraindications
` Do not administer cabazitaxel if the neutrophil count is less than or equal to 1,500/mm3.
` Do not administer cabazitaxel in patients with a history of severe hypersensitivity reactions to
`cabazitaxel or other drugs formulated with polysorbate 80.
`
`
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
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`Warnings and Precautions
`1. Neutropenia (Boxed Warning)
` Five patients with grade 4 neutropenia, one with febrile neutropenia, experienced fatal
`infections. One additional death was attributed to neutropenia without a documented
`infection.
` G-CSF may be administered to decrease the risk of neutropenia complications.
` Primary prophylaxis with G-CSF should be considered in patients at high risk who are pre-
`disposed to increased complications from prolonged neutropenia. This includes: patients
`>65 years old, poor performance status, previous episodes of febrile neutropenia, extensive
`prior radiation ports, poor nutritional status, or other serious co-morbidities.
` Monitor complete blood counts weekly during Cycle 1 and before each subsequent cycle to
`assess if a dose adjustment is needed.
` If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one
`week) despite the use of G-CSF, reduce the dose of cabazitaxel to 20 mg/m2 and restart
`treatment when the neutrophil count recovers to a level > 1,500/mm3.
`
`
`2. Hypersensitivity Reactions (Boxed Warning)
` Pre-medicate all patients with an IV antihistamine, corticosteroid, and H2 blocker prior to
`administration of cabazitaxel.
` Observe patients closely for hypersensitivity reactions especially during the 1st and 2nd
`infusions. Hypersensitivity reactions may occur within a few minutes of starting the
`cabazitaxel infusion; facilities and equipment for treating bronchospasm and hypotension
`should be available.
` Severe hypersensitivity reactions, including generalized rash/erythema, hypotension, and
`bronchospasm require discontinuation of the cabazitaxel infusion and appropriate therapy.
`
`
`3. Gastrointestinal Symptoms
` Nausea, vomiting, and severe diarrhea have been reported
` Death as a result of severe diarrhea and electrolyte imbalance occurred in clinical trials.
` Patients with severe diarrhea should be treated with rehydration and antidiarrheals as
`needed.
` Treatment delay or dose reduction may be needed for Grade ≥3 diarrhea.
`
`
`4. Renal Failure
` Renal failure was reported in clinical trials.
` Four cases of renal failure resulted in death.
` Most cases are associated with sepsis, dehydration, or obstructive uropathy.
`
`
`5. Hepatic Failure
` Patients with impaired hepatic function were excluded from clinical trials. No dedicated
`trials in patients with hepatic impairment have been conducted.
` Hepatic impairment increases the risk of severe and life-threatening complications in
`patients receiving other drugs in the taxane class.
` Do not administer cabazitaxel to patients with hepatic impairment (total bilirubin ≥ the
`Upper Limit of Normal, or AST and/or ALT ≥1.5 times the Upper Limit of Normal).
`
`
`
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
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`6. Elderly
` 2% of patients under age 65 and 6% of patients greater than or equal to age 65 died of
`causes other than disease progression within 30 days of the last cabazitaxel dose. Patients
`greater than or equal to age 65 are more likely to experience certain adverse reactions
`including neutropenia and febrile neutropenia.
`
`
`7. Pregnancy
` Pregnancy Category D; cabazitaxel may cause fetal harm when administered to pregnant
`women
` Cabazitaxel is embryotoxic, fetotoxic, and abortifacient at exposure levels in rats and
`rabbits significantly lower than those expected at recommended human dosage levels.
` There are no adequate or well controlled trials in pregnant women. Inform patient of the
`potential harm to the fetus if administered during pregnancy or if the patient becomes
`pregnant while receiving cabazitaxel.
`
`
`8. Nursing Mothers
` Cabazitaxel and its metabolites are excreted in the breast milk of lactating rats. It is not
`known if it is excreted in human breast milk. Because of the potential for serious adverse
`reactions in nursing infants, a decision should be made to either discontinue nursing or
`discontinue the drug taking into account the benefit versus risk for the mother.
`
`
`Postmarketing Safety Experience (Optional)
`No data
`
`Sentinel Events
`No data on sentinel events in the VHA database or on the Joint Commission web site.
`
`Look-alike / Sound-alike (LA / SA) Error Risk Potential
`
`As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs.
`Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-
`Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the
`following drug names may cause LASA confusion:
`LA/SA for generic name Cabazitaxel: docetaxel, paclitaxel
`LA/SA for trade name Jevtana: Jantoven, Januvia
`Drug Interactions
`
`Drug-Drug Interactions
` No formal drug-drug interaction trials have been conducted
` Prednisone or prednisolone at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
` Drugs that may Increase cabazitaxel plasma concentrations
`o CYP3A4 Inhibitors: cabazitaxel is primarily metabolized through CYP3A, but there
`are no formal trials of concomitant use with strong CYP3A4 inhibitors.
`o Strong inhibitors (e.g. ketoconazole, intraconazole, clarithromycin, atazanavir,
`indivavir, nefazodone, nelfinavir, ritoniavir, saquinavir, telithromycin, voriconazole)
`
`
`
`
`Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
`Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits
`Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged
`under the provisions of 38 U.S.C. 5705 and its implementing regulations. In such cases, this material shall not be
`disclosed to anyone without authorization as provided for by that law or its regulations. The statute provides for fines up
`to $20,000 for unauthorized disclosure.
`
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`are expected to increase cabazitaxel concentrations and co-administration should be
`avoided.
`o Exercise caution with the co-administration of moderate CYP3A4 inhibitors.
` Drugs that may Decrease cabazitaxel plasma concentrations
`o CYP3A4 inducers: There are no formal drug interaction trials of concomitant use
`with strong CYP3A4 inducers.
`o Strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin,
`rifapentin, and phenobarbital) are expected to decrease cabazitaxel concentrations
`and co-administration should be avoided.
`o Patients should also avoid co-administration of St